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Metallohelices with activity against cisplatin-resistant cancer cells; does the mechanism involve DNA binding?
Brabec, V. Howson, S.E. Kaner, R.A. Lord, Rianne M. Malina, J. Phillips, Roger M. Abdallah, Qasem M.A. McGowan, P.C. Rodger, A. Scott, P.
Brabec, V.
Howson, S.E.
Kaner, R.A.
Lord, Rianne M.
Malina, J.
Phillips, Roger M.
Abdallah, Qasem M.A.
McGowan, P.C.
Rodger, A.
Scott, P.
Publication Date
2013-12
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© 2013 RSC. Open access. Reproduced in accordance with the publisher's self-archiving policy.
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Abstract
Enantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that
of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian
carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line
HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower
than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is
probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and
intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy
and supported by circular/linear dichroism in solution. Selectivity for 50-CACATA and 50-CACTAT
segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are
stabilised, and remarkably only the L metallo-helix enantiomer stabilizes T-shaped 3WJs during gel
electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide
duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the
number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible
metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the
cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all
compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage
occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase,
and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together
these screening and mechanistic results are consistent with the more rigid helices acting via a DNA
binding mechanism while the flexible assemblies do not.
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Citation
Brabec V, Howson SE, Kaner RA, Lord RM, Jaroslav M, Phillips RM, Abdallah QMA, McGowan PC, Rodger A and Scott P (2013) Metallohelices with activity against cisplatin-resistant cancer cells; does the mechanism involve DNA binding. Chemical Science. 4(12): 4407-4416.
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